Alpha-norsteroids



United States Patent 3,393,230 A-NORSTEROKDS Josef Fried, Princeton, N.J., assignor, by mesne assign- ABSTRACT OF THE DISCLOSURE This invention relates to a novel compound having the formulae CH; Z G Hz Z (3:0 (3:0 W1 m R, N l a O W O- I l x C H: Z X C Hz Z C=O =0 W m I (Liz O and f Hz O O- Y wherein X is lower 'alkyl; R is hydrogen; R is hydroxy; and together R and R is 0x0 (0:); and Z is selected from the group consisting of hydrogen, hydroxy, halogen and acyloxy wherein the acyl radical is of a hydrocarbon carboxylic acid of less than twelve carbon atoms. These compounds possess anti-androgenic activity and thus may be employed in the treatment of hyperandrogenic acne.

This invention relates to and has for its objects the provision of new physiologically active steroids, methods for their production, and novel intermediates useful in the preparation thereof.

The novel final products of the instant invention may be represented by the formulae CHZZ (IJIHZ \/\l l I l I on; on; O O- I I X X 3,393,230 Patented July 16, 1968 wherein R is hydrogen; R is hydroxy; and together R and R is 0x0 (0:); X is lower alkyl (e.g. methyl) and Z is selected from the group consisting of hydrogen, hydroxy, acyloxy and halogen (e.g. chloro, fluoro, bromo or iodo).

The preferred acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g. acetic, propionic, butyric and tert.-pentonic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids .(e.g. benzoic and toluic acid), the monocyclic aryl lower alkanoic acids (e.g. phenacetic and fi-phenylpropionic acid), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

The products of this invention are physiologically active compounds which possess antiandrogenic activity and thus may be employed in the treatment of hyperandrogenic acne, for which purpose they may be administered, the dosage being adjusted for the relative potency of the particular steroid and the requirements of the patient.

The final products of this invention may be prepared by the processes of this invention, which entail a number of steps starting with the compounds represented by the following formulae COOB COOB

it n

Wit,

wherein B is lower alkyl and R and R are as hereinbefore defined. The compounds which may be employed as starting materials in the practice of this invention may be prepared according to the procedures set forth in my copending applications Ser. No. 212,154, filed July 24, 1962, now Patent No. 3,170,919 and Ser. No. (K358) filed on even date herewith, now Patent No. 3,271,390, and include such compounds as methyl 14-methyl-A-nor- A -androstene 3,11 dione-l7 3-carboxylate; methyl 14- methyl-A-nor 13 androstadiene-3-one-l7fi-carboxylate; methyl 14-methyl A nor-A -androstene-l 15-01-3- one-17/3-carboxylate; methyl 14 methyl-A-nor-A -androstem-3,11,1S-trione-17fi-carboxylate; methyl 14 methyl- A-nor-A -androstadiene-3,l5-dione-17B carboxylate; and methyl 14 methyl-A-nor-A -androstene-1Idol-3, 15- dione-17fl-carboxylate.

The process of the instant invention may be represented by the following equations, wherein X, R, R and Z are as hereinbefore defined:

COOB 00013 R K my ,J l

I BZCHrs; R':OH; RZII III BICHa II BICHs; R&R=O=

CIOOB COOB R I I g I I t a, by 2 CH N I IV BICHa, RZH, :OH VI B CHa V BzcHs; R&R'=0= COOB COOB R K II I I 5 I I CH CH VII BICIIa; RzI-I; ':OH IX BZCIIs VIII 13:01-13; R -n'= GOA GOA R I I I /\I/ CH3 CH3 G H X Rzl-I; R'zOH; Azhalide (Cl, Br) XII Azhallde XI R&R= Azhalide (C1, 131) (CI, B1)

CHN]

COO

In the first step of the process of this invention, the ll-substituted A-nor-M-androstenes (Compounds A) and the A-nor-A -androstadienes (Compounds B) starting materials are reacted with a diazoalkane (e.g. diazomethane) in the presence of a metal halide (e.g. aluminum chloride) to yield the respective pyrazoline derivatives thereof (Compounds C and D) which are new compounds of this invention.

Compounds C and D may then be heated at temperatures above their respective melting points to yield the respective 6-methyl-A -androstene (Compounds E) and the 6 methyl A1901) androstadienes (Compounds P), which are also new compounds of this invention.

Compounds E and F may then be treated with an acid halide, for example, oxalyl chloride, to obtain the corresponding ll-substituted 6-methyl-A-nor-A -androstenel7-carboxylic acid halides (Compounds G) and the 6- methyl-A-nor-A- -androstadiene 17 carboxylic acid chlorides (Compounds H) respectively, which are also new compounds of this invention.

These acid chloride compounds (Compounds G and H) are then converted to their respective diazoketone-6- methyl-A-nor-A pregnenes (Compounds J) and diazoketone-6 methyl A nor A pregnadienes (Compounds K), which are also new compounds of this invention, by treatment with an ethereal solution of diazomethane.

In order to obtain the final products of this invention which are oxygenated in the 21-position (i.e. Z is acyloxy or hydroxy). Compounds J and 'K are treated at elevated temperature with a fatty acid, for example, acetic, propionic or butyric acid, to yield the 21-esters of ll-substituted-6-methyl-A-norA -pregnenes (Compounds L) and 6-methyl-A-nor-A -pregnadienes (Compounds M),

which are also new compounds of this invention. Alternatively, Compounds L and M (wherein Z is acyloxy) may be obtained by first treating Compounds J and K with a hydrohalide, for example, hydrochloric acid, to yield the 2l-halogenated-A-nor-pregnenes (Compounds L and M, wherein Z is halide), which are also new compounds of this invention, and then substituting the 21-halide-A-norpregnenes as by treatment with potassium iodide and potassium acetate to yield the respective 21-acyloxy-A- nor-pregnenes (Compounds L and M). To obtain the 21- hydroxy-A-nor-pregnene compounds of this invention (Compounds L and M, wherein Z is hydroxy), the 21- acyloxy compounds are treated with a base, such as potassium carbonate. The 21-hydroxy-6-methyl-A-n0r-pregnenes (Compounds L and M, wherein Z is hydroxy) are also new compounds of this invention.

To obtain the final compounds of this invention, which are not oxygenated in the 2l-position (i.e. wherein Z is hydrogen or halogen), Compounds J and K are first treated with hydriodic acid to yield the 21-unsubstituted- A-nor-pregnenes (Compounds L and M, wherein Z is hydrogen), which are also new compounds of this invention.

The 21-halogenated compounds are obtained as set forth hereinabove, i.e., by treatment of Compounds J and K with a hydrohalide, e.g., hydrochloric acid. It should be noted that when the l5-keto starting materials are employed in the practice of this invention, the final products thereof and the intermediates produced thereby will all be the -keto derivatives of the compounds set forth hereinabove. These compounds are also new compounds of this invention.

The invention may be further illustrated by the following examples:

Example 1.-Methyl 14-methyl-5,6-pyrazolino-A- norandrostane-3,l l-dione-l7 8-carboxylate (II) To a suspension of 50 mg. of finely powdered methyl 14 methyl A nor A androstene 3,11 dionel7fi-carboxylate (I) in 30 ml. of ethereal diazomethane solution is added at room temperature, in portions, a total of mg. of aluminum chloride which had been aged by leaving it exposed to the atmosphere for 5-1O minutes. The total reaction time is one hour and thirty minutes. The excess diazomethane is then destroyed by the addition of two drops of glacial acetic. The mixture is washed with water and the ether extract evaporated to dryness in vacuo. The resulting residual mixture is purified by preparative thin layer chromatography on .activity V neutral alumina using chloroform as the moving phase. Two zones are obtained, designated as A and B. The elution of zone A furnishes after concentration 21 mg. of material, M.P. ZOO-201, which is identified as starting material. Elution of zone B furnishes after crystallization from methanol 9 mg. of methyl 14- methyl 5,6 pyrozolino A norandrostane 3,11- dione-17B-carboxylate which melts with decomposition at 176-178"; [a] +360 (c., 0.28 in chloroform);

KBr m...

Analysis-Calcd. for C22H3DO4N2 (386.48): C, 68.37; H, 7.32. Found: c, 53.43; H, 7.81.

Example 2.Methyl 14-methyl-5,6-pyrazolino-A- nor-A -androstene-3-one-17B-carboxylate Example 3.Methyl 14-methyl-5,6-pyrazolin0-A- nor-androstane-l1fl-ol-3-one-1713-carboxylate Following the procedure set forth in Example 1, but substituting an equivalent amount of methyl 14-methyl- A-nor-A -androstene-1113-01-3 one 17o carboxylate for methyl 14 methyl A nor A androstene 3,11- dione-17fi-car-boxylate, there is obtained methyl 14-methyl 5,6 pyrazolino A norandrostane 11 3 o1 3- one-17,8-carboxylate.

Example 4.Methyl 6,l4-dimethyl-A-nor-A -androstene-3,11-dione-17fi-carboxylate (III) Five mg. of methyl 14 methyl 5,6 pyrazolino A- norandrostane 3,11 dione 175 carboxylate (II) was placed into an evacuated tube and heated in a bath at a temperature of -170". The contents of the tube melts and sublimed to colder portions. The tube is then cooled, the bottom cut off and the sublimate recrystallized from methanol. The pure methyl 6,14 dimethyl A nor A androstene 3,11 dione 17,6 carboxylate (III) melts at 172-174";

x 32 255 m (E=8,600) x55; 5.75, 5.86, 6.10,.

Example 5.Methyl 6,14-dimethyl-A-nor-A -androstadiene-3-0ne-17,8-carboxylate Following the procedure set forth in Example 4 but substituting an equivalent amount of methyl 14-methyl- 5,6-pyrazolino-A-nor-A -androstene 17B carboxylate for methyl 14-methyl-5,6-pyrazolino-A-norandrostane- 3,11 dione-17B-carboxylate, there is obtained methyl 6,14-dimethyl-A-nor A androstadiene-3-one-17flcarboxylate.

Example 6.Methyl 6,14-dimethyl-A-nor-A -androstene- 11,8-01-3-one-Inf-carboxylate Following the procedure set forth in Example 4, but substituting an equivalent amount of methyl 14-methyl- 5,6 pyrazolino A nor-A -androstene-11B-ol-3-one-17ficarboxylate for methyl 14-methyl-A-nor-A -androstene- 3,20-dione-Nil-carboxylate, there is obtained methyl 6,14- dimethyl-A-nor A androstene 11B ol 3 one-17B- carboxylate.

Example 7.6, 14-dimethyl-A-nor-A -androstene-3,1 1-

dione-17fl-carboxylic acid Example 8.6,14-dimethyl-A-nor-A -androstadiene- 3-one-17/3-carboxylic acid Following the procedure set forth in Example 7 but substituting an equivalent amount of methyl 6,14-dimethyl- A-nor-A -androstadiene 3 one-17/i-carboxylate for methyl 6,14-dimethyl-A-nor-A -androstene 3,11 dionel7 8-carboxylate, there is obtained 6,14-dimethyl-A-nor- A -androstadiene-3-one-17B-carboxylic acid.

Example 9.6, 14-dimethyl-A-nor-A -androstene-1 lfl-ol- 3-one-l9fi-carboxylic acid Following the procedure in Example 7 but substituting an equivalent amount of methyl 6,14-dimethyl-A-nor-A androstene-11B-ol-3-one-Nil-carboxylate for methyl 6,14- dimethyl-A-nor-A -androstene-3,1 1-dione-l7/3-carboxylate, there is obtained 6,14-dimethyl-A-nor-A -androstene-l1B- ol-3-one-l9fl-carboxylic acid.

7 Example l0.6, 14-dimethyl-A-nor-A -androstene-3,1 ldione-l7 3-carboxylic acid chloride To a suspension of vacuum dried 6,14-dimethyl-A-nor- A -androstene 3,11 dione-l7 3-carboxylic acid in anhydrous benzene is added with stirring redistilled oxalyl chloride. After 30 minutes all the acid has dissolved and the solution is allowed to remain at room temperature for an additional 40 minutes. Upon the removal of the solvent in vacuo there remains a crystalline solid to which is added anhydrous benzene and the latter removed again in vacuo, thus yielding 6,14-dimethyLA-nor-Afi-androstene-3,11-dione-l7B-carboxylic acid chloride.

Example 1l.-6,14-dimethyl-A-nor-A -androstadiene- 3-one-17fi-carboxylic acid chloride Following the procedure set forth in Example but substituting an equivalent amount of 6,14-dimethyl-A- nor-A -androstadiene-3-one-l7 3-carboxylic acid for 6,l4-dimethyl-A-nor-A androstene 3,11 dione-17fl-carboxylic acid there is obtained 6,14-dimethyl-A-nor- A -androstadiene-3-one-l7B-carboxylic acid chloride.

Example 12.6,14-dlmethyl-A-nor-A androstene-l lfi-ol- 3-one-17fl-carboxylic acid chloride Following the procedure set forth in Example 10 but substituting an equivalent amount of 6,14-dimethyl-A- nor A androstene-l1,8-ol-3-one-17fi-carboxylic acid for 6,14-dimethyl-A-nor-A -androstene 3,11 dione-17B-carboxylic acid there is obtained 6,14-dimethyl-A-norA androstene-l1,8-ol-3-one-17fl-carboxylic acid chloride.

Example 13 .6, 14-dimethyl-2 l-diazo-A-nor-A pregnene-3,1 1,20-trione A solution of 6,14-dimethyl-A-nor-A -androstene-3,l1- dione-l7fi-carboxylic acid chloride in anhydrous benzene is added at 0 C. to a concentrated distilled solution of diazomethane in ether. The mixture is allowed to warm up to room temperature and after a total reaction time of 1 /2 hours it is filtered from flocculent polyethylene and evaporated to dryness in vacuo. The resulting crystalline residue is recrystallized from methanol and furnishes 6,14-dimethyl-2 l-diazo-A-n0r-A -pregnene-3 ,11,20-trione.

Example 14.6,14-dimethyl-2l-diazo-A-nor-A pregnadiene-3 ,20-dione Following the procedure set forth in Example 13 but substituting an equivalent amount of 6,14-dimethyl-A-nor- A -androstadiene3-one-l7fl-carboxylic acid chloride for 6,14-dimethyl-A-nor-A -androstene 3,11 dione-l7flcarboxylic acid chloride there is obtained 6,14-dimethyl- 2l-diazo-A-nor-A -pregnadiene-3,ZO-dione.

Example .-6, l4-dimethyl-2 l-diazo-A-nor-A -pregnene- 11 ,8-ol-3,20-dlone Following the procedure set forth in Example 13 but substituting an equivalent amount of 6,14-dimethyl-A- nor-A -androstene-115-ol-3-one-17B-carboxylic acid chloride for 6,l4-dimethyl-A-nor-A -androstene-3,ll-dione- 17fl-carboxylic acid chloride there is obtained 6,14-dimethyl-21-diazo-A-nor-A -pregnene-l 15-ol-3,20-dione.

Example 16.-6, l4-dimethyl-21-chloro-A-nor-A pregnene-3,'11,20tri0ne To a solution of 6,14-dimethyl-21-diazo-A-nor-A -pregnone-3,11,20-trione is added at 0 C. a saturated solution of hydrogen chloride in chloroform. The mixture is allowed to remain at 0 C. for 20 minutes after which time it is extracted with dilute sodium bicarbonate. The chloroform extract is dried over sodium sulfate, evaporated to dryness and the residual crystalline recrystallized from methanol yielding 6,14-dimethyl-21-chloro-A- nor-A -pregnene-3,1 1,20-trione.

Similarly, following the procedure of Example 16 but substituting hydrogen bromide for the hydrogen chloride 8 there is obtained 6,14-dimethyl-2l-bromo-A-nor-M-pregnene-3,l1,20-trione.

Similarly, when a limited amount'of hydrogen iodide is substituted for the hydrogen chloride, 6,14-dimethyl-21- iodo-A-nor-A -pregnene'3,11,20-trione is obtained.

Example 17.-6,'14-dimethyl-2l-chloro-A-nor-A pregnadiene-3,20-dione Following the procedure set forth in Example-16 but substituting an equivalent amount of 6,14-dimethyl-2ldiazo-A-nor-A -pregnadiene-3,2O-dione for 6,14-dimethyl-21-diazo-A-nor-A -pregnene-3,11,20'-trione there is obtained 6,14 dirnethyl-Z1-chloro-A-norA pregnadiene3,20-dione.

Example 18.6,14-dimethyl-2l-chloro-A-nor-A pregnene-l lB-ol-3,20-dione Following the procedure set forth in Example 16 but substituting an equivalent amount of 6,14-dimethyl-2ldiazo-A-nor-M-pregnene-l1,3-ol-3,20-dione for 6,14-dimethyl-2l-diazo-Anor-A -pregnene-3,l1,2Otrione there is obtained 6,14 dimethyl-2l-chloro-A-nor-A -pregnenediene-3,20-dione.

Example 19.6,14-dimethyl-A-nor-A -pregnene- 3,11,20-trione To a solution of 6,14-dimethyl-21-diazo-A-nor-A -pregnene-3,11,20-trione in chloroform is added under a blanket of carbon dioxide freshly distilled aqueous hydriodic acid. The mixture is thoroughly mixed by shaking for 3 minutes at room temperature, poured into water and chloroform and the chloroform solution extracted with dilute sodium bicarbonate with the addition of a small amount of sodium bisulfite. The chloroform extract is then washed with Water, dried over sodium sulfate and evaporated to dryness in vacuo and the residue crystallized from methanol to yield 6,l4-dimethyl-Anor-A pregnene-3,1 1,20-trione.

Example 20.6,14-dirnethyl-A-nor-A -pregnadiene- 3,20-dione Following the procedure set forth in Example 19 but substituting 6,14-dimethyl-2l-diazo-A-nor-A -pregnadiene-3,20-dione for 6,14-dimethyl-21-diazo-A-nor-A pregnene 3,11,20 trione yields 6,14-dimethyl-A-nor- A -prewadiene-3,20-dione.

Example 21.6,14-dimethyl-A-nor-A -pregnenellfi-ol-3,20-dione Following the procedure set forth in Example 19 but substituting an equivalent amount of 6,14-dimethy1-21- diazoA-nor-A -pregnene-1lB-ol-3,20-dione for 6,14-dimethyl-21-diazo-A-nor-A -pregnene-3, l 1,20-trione yields 6, 14-dimethyl-A-nor-A pregnene-l 1 18-01-3,20-dione.

Example 22.6, 14-dimethyl-A-nor-A -pre gnene-Z 1 -ol- 3,11,20-trione-21-acetate Example 23.-6,14-dimethyl-A-n0r-A -pregnadiene- 21-ol-3,20-dione-2l-acetate 7 Following the procedure set forth in Example 22. but

substituting 6,14-dimethyl-21-diaz0-A-nor-A F -pregna- 9 diene-3,20-dione for 6,14-dimethyl-2l-diazo-A-nor-A pregnene 3,11,20 trione yields 6,14 dimethyl-A-nor- A -pregnadiene-Zl-ol-3,ZO-dione-Zl-acetate.

Example 24.--6,14-dimethy1-A-nor-A -pregnene- 11,8,21-diol-3,20-dione-21-acetate Following the procedure set forth in Example 22 but substituting 6,14 dimethyl-Z1diazo-A-nor-A -pregnene- 1 15-ol-3,20-dione for 6,14-dimethyl-2 l-diazo-A-nor-A preguene-3,11,20-trione yields 6,14-dimethyl-A-nor-A pregnene-l 15,2 l-diol-3,20-dione-2 l-acetate.

Example 25.6,14-dimethyl-A-nor-A -pregneue- 21-01-3, l 1,20-trione Example 26.-6,l4-dimethy1-A-nor-A -pregnene- 2 l-ol-3,20-dione Following the procedure set forth in Example 25 but substituting 6,14-dimethyl-A-nor-A -pregnadiene-Zlol-3,20-dione-2l-acetate for 6,l4-dimethyl-A-nor-A -pregnene-2l-ol-3,11,20-trione 21 acetate there is obtained 6,14-dimethyl-A-nor-A -pregnene-Zl-ol-3,2O-dione.

Example 27.6,14-dimethyl-A-nor-A pregnene- 11p,21-diol-3,20-dione Following the procedure set forth in Example 25 but substituting 6,14-dimethyl-A-nor-A -pregnene-11,9,21-dil- 3,20-dione 21-acetate for 6,14-dimethyl-A-nor-A -pregnene-21-ol-3,11,20-trione 21 acetate there is obtained 6,14 dimethyl-A-nor-A -pregnene-11fi,21-diol-3,20-dione.

The invention may be variously otherwise embodied within the scope of the appended claims.

10 What is claimed is: 1. A compound selected from the group consisting of steroids of the formula wherein X is lower alkyl; R is hydrogen; R is hydroxy; and together R and R is 0x0 (0:); and Z is selected from the group consisting of hydrogen, hydroxy, halogen and acyloxy wherein the acyl radical is of a hydrocarbon carboxylic acid of less than twelve carbon atoms.

References Cited UNITED STATES PATENTS 3,170,919 2/1965 Fried 260-586 LORRAINE A. WEINBERGER, Primary Examiner.

RICHARD K. JACKSON, Examiner.

V. GARNER, Assistant Examiner. 

